Phenytoin Therapy Research Articles

Valproate metabolites in high-dose valproate plus phenytoin therapy.

We wished to determine the relation between liver function, beta-, and omega-, and omega-1-oxidation metabolites and 4-en-valproate (VPA). We measured the serum levels of VPA and its metabolites in children and adolescent receiving high-dose VPA plus phenytoin (PHT) therapy using gas chromatography-mass spectrometry with selected ion monitoring (GC/MS/ SIM). In high-dose VPA plus PHT polytherapy, the total VPA serum concentration was distinctly low, the concentrations of total beta-oxidation metabolites were decreased, the percentage values of VPA (percent of VPA) of total beta-oxidation metabolites were increased, and the E-2-en-VPA/3-keto-VPA ratios were decreased, as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT polytherapy, 4-en-VPA (microM) was decreased and the concentrations of [omega + (omega-1)]-oxidation metabolites (microM) were decreased as compared with those in high-dose VPA monotherapy. In high-dose VPA plus PHT, serum glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and lactic dehydrogenase (LDH) did not correlate significantly with the ¿beta/omega + (omega-1)¿ metabolites ratio and 4-en-VPA levels, but serum GOT, GPT, and LDH were increased as compared with those in high-dose VPA therapy. We were not able to establish a significant relation between the formation of metabolites of VPA metabolites and liver dysfunction in patients receiving high-dose VPA and PHT concurrently. Metabolic levels do not appear to be a reliable predictor of hepatotoxicity in children receiving pharmacological antiepileptic drug (AED) therapy.

Pharmacokinetic Interactions Between Antiepileptic Drugs

Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial beta-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

Reduced plasma nisoldipine concentrations in phenytoin-treated patients with epilepsy.

To assess whether phenytoin affects the pharmacokinetics of the dihydropyridine calcium antagonist nisoldipine. Twelve patients with epilepsy receiving chronic phenytoin therapy and 12 healthy control subjects matched for age and gender received a single oral dose of nisoldipine (40 and 20 mg, respectively). Blood samples were collected for up to 48 h for estimation of plasma nisoldipine levels by capillary gas chromatography. Mean plasma nisoldipine concentrations were much lower in the patients. Geometric means for areas under the concentration-time curve (AUC0-tn) normalized to a 20-mg dose were 1.6 micrograms/L/h (95% confidence intervals, 0.6-3.8 micrograms/L/h) in the patients compared with 15.2 (10.7-21.6) micrograms/L/h in control subjects (p < 0.002). These results suggest that phenytoin increases the first-pass metabolism of nisoldipine to a clinically important extent. In view of the magnitude and variability of interaction, use of nisoldipine in patients receiving chronic phenytoin therapy is contraindicated.

Gingival enlargement induced by drugs.

Gingival enlargement, an abnormal growth of the periodontal tissue, is mainly associated with dental plaque-related inflammation and drug therapy. Its true incidence in the general population is unknown. Gingival enlargement produces aesthetic changes, pain, gingival bleeding and periodontal disorders. Although gingival overgrowth has been traditionally recognised as an adverse effect of phenytoin therapy, it has recently been reported in association with the use of cyclosporin and calcium antagonists. These 3 classes of drugs produce important changes in fibroblast function, which induce an increase in the extracellular matrix of the gingival connective tissue. In the majority of those patients for whom dosage reduction, or drug discontinuation or substitution is not possible, and for whom prophylactic measures have failed, surgical excision of gingival tissue remains the only treatment of choice.

Phenytoin Toxicity Associated With Ticlopidine Administration

A case of phenytoin sodium toxicity that appeared to be related to the administration of ticlopidine hydrochloride was recently observed at the Prescott Veterans Affairs Medical Center in Arizona. Report of a Case. A 71-year-old man had been taking ticlopidine for treatment of transient ischemic attacks. Concurrent medications included phenytoin sodium (350 mg/d), phenobarbital (90 mg/d), and cholestyramine resin (4 g at bedtime). The dosage of the phenytoin therapy had not been changed over the last 6 years (serum phenytoin concentrations, 60 to 80 μmol/L [15 to 20 mg/L]). A serum phenytoin concentration of 60 μmol/L (15 mg/L) was noted 2 weeks before ticlopidine therapy was initiated. The dosage of the phenobarbital therapy had not been changed for more than 2 years. After 1 month of ticlopidine hydrochloride therapy (250 mg twice daily), the patient began complaining of difficulty in walking and bilateral leg weakness. Serum concentrations of phenytoin and

Phenytoin protein binding and dosage requirements during acute and convalescent phases following brain injury.

To longitudinally evaluate unbound and total serum phenytoin concentrations during intravenous phenytoin maintenance dosage and to determine the relationship among phenytoin protein binding, serum albumin, and unbound fatty acid concentrations in patients with head injuries during intensive care unit (ICU) and convalescent care. Serum albumin and phenytoin unbound fraction were determined twice weekly during ICU and convalescent care in 10 patients receiving phenytoin following acute brain injury. Phenytoin protein binding was also determined in 10 healthy control subjects. Longitudinal serum phenytoin concentrations associated with dosage adjustments targeted to achieve unbound phenytoin serum concentrations between 1.0 and 2.0 mg/L were documented during ICU and convalescent care. Longitudinal phenytoin binding was correlated with serum albumin and unbound fatty acid concentrations in neurotrauma patients. ICU patients received intravenous therapy for a mean of 15.0 days. The mean +/- SD initial phenytoin intravenous dosage regimen of 6.0 +/- 0.7 mg/kg/d resulted in mean +/- SD total and unbound phenytoin concentrations of 3.2 +/- 2.3 and 0.3 +/- 0.2 mg/L. Two patients had seizures associated with low phenytoin concentrations. Four patients continued to receive oral phenytoin therapy during convalescent care; phenytoin dosage requirements decreased over time in these patients. During acute and convalescent care, the phenytoin unbound fraction ranged from 6.0% to 18.3% and correlated with albumin (r2 = 0.61, p < 0.0001) but did not correlate with unbound fatty acid concentrations. The mean phenytoin unbound fraction was 10.1% and 8.9% for the ICU and convalescent patients with brain injuries, respectively, and was 7.0% for the healthy volunteers. Phenytoin protein binding was significantly correlated with albumin and was more variable in ICU and convalescent patients with brain injuries than in healthy volunteers. The high dosage requirements and subtherapeutic unbound phenytoin concentrations observed during acute care are best explained by increased metabolism. Phenytoin dosage requirements decreased during convalescence.

Pseudo valproate-induced hypofibrinogenemia

An almost 6-year-old boy with a history of prematurity, posthemorrhagic hydrocephalus, cerebral palsy, and epilepsy was admitted for treatment of ureteral colic. The patient had experienced episodes of intense abdominal pain with vomiting and diaphoresis for 2 months. An intravenous pyelogram demonstrated a 6-mm stone in the right ureter, causing severe right ureteropyelocaliectasis. A ventriculoperitoneal shunt had been placed at about 1 year of age and the patient had undergone selective dorsal rhizotomy. The patient was receiving valproate at a dosage of 500 mg/day. A valproate level determination was 101 kg/ml. In anticipation of urologic surgery, coagulation studies were obtained. Prothrombin time was 14.9 s (normal 9.8 to 13.2) with an International Normal Ratio (INR) of 1.26 (normal 0.8 to 1.2), partial thromboplastin time was 25.4 s (normal 21.4 to 34), and thrombin time was elevated at 73.3 s (normal 13 to 20). Two fibrinogen level determinations were less than 50 mg/dl (normal 145 to 375). Total protein, albumin, aspartate transaminase, and gamma glutamyl transferase values were normal. Repeated prothrombin time was 15.4 s (INR 1.39), partial thromboplastin time 30.8 s, and thrombin time 43.2 s. Factor VII was decreased at 62% (normal 70 to 130). Clauss fibrinogen was 50 mg/dl (normal 170 to 370). In view of concerns regarding valproate-induced fibrinogen depletion [l-4], valproate therapy was discontinued and phenytoin therapy initiated. Coagulation studies on the patient’s mother revealed an elevated thrombin time of 54 s. Prothrombin time and partial thromboplastin time were normal at 12.2 s (INR 1.05) and 25.8 s, respectively. In the patient, fibrinogen degradation products were elevated at 120 p,g/ml (normal 0 to 10). Fibrinogen crossed immunoelectrophoresis (CIEP) study revealed a ratio of 0.57 between the highest point of the patient’s peak and the standard peak. The highest point of the patient’s peak moved a slightly shorter

Intractable Hiccup in Two Severely Handicapped Patients during Phenytoin Therapy

Intractable Hiccup in Two Severely Handicapped Patients during Phenytoin Therapy

Multiple Myeloma Associated with Phenytoin (Diphenylhydantion) Therapy

Multiple Myeloma Associated with Phenytoin (Diphenylhydantion) Therapy

Concomitant phenytoin therapy doubles the osteogenic and densitometric effect of fluoride therapy in osteoporosis

Concomitant phenytoin therapy doubles the osteogenic and densitometric effect of fluoride therapy in osteoporosis

Comparing the Cognitive Effects of Phenytoin and Carbamazepine in Long‐Term Monotherapy: A Two‐Year Follow‐Up

We compared the cognitive effects of randomly prescribed phenytoin (PHT) and carbamazepine (CBZ) therapy on newly diagnosed patients with epilepsy in a 2-year parallel group follow-up study. Fifteen patients were receiving PHT and 16 were receiving CBZ. Neuropsychological assessments were conducted before the treatment and after 6 and 24 months of steady-state drug therapy. Differential effects of PHT and CBZ during follow-up were observed in 3 of 32 measurements. PHT appeared to have negative effects on visually guided motor speed of both hands. In addition, the performance of the PHT group as compared with the CBZ group developed less positively in one visual memory task. The development of mood as measured by Profile of Mood States (POMS), was quite similar in both drug groups; Tension, Depression, and Bewilderment decreased and Vigor increased during the follow-up. The results suggest that the long-term effects of PHT as compared with those of CBZ on cognition are few and restricted mainly to some visually guided motor functions. The effects of PHT on cerebellar function as a possible mechanism for these changes is discussed.

Clinical physiological study of the therapeutic effects of phenytoin in acute alcohol withdrawal and the asthenic-autonomic syndrome in patients with chronic alcoholism

The effects of diphenylhydantoin [phenytoin (PHT)l on both the acute withdrawal syndrome (AWS) and the asthenic-autonomic syndrome associated with chronic alcoholism were evaluated in a single-blind, controlled, clinical, and comprehensive multiparameter psychophysiological and neurophysiological study. Twenty-four patients were treated with PHT (100 mg, PO, tid) and our standard detoxification therapy (intravenous fluids and vitamins as an antihistamine and a vasodilator; cognitive psychotherapy; and occupational therapy) and their progress was compared to that of 12 patients receiving only our standard detoxification therapy. The use of PHT and standard detoxification therapy resulted in an amelioration or cessation of the main symptoms of acute alcohol withdrawal within a mean of 3 ± 1 days. Vital fear, psychomotor excitation, sense of shortness of breath, pronounced chill-like state, and pronounced perspiration disappeared within 3 days. In the control group, the same improvements were found in a mean of 11 ± 3 days. After the acute withdrawal period, PHT (50–100 mg, bid-tid) was continued in all 24 patients of the PHT group to evaluate its effects on the asthenic-autonomic syndrome. PHT's most marked therapeutic effects (improvements in mood, aggression, ability to react appropriately to surroundings, attention, active vigilance, and autonomic parameters) were seen in eight patients with the sympathetic-adrenal type of autonomic disorders. Dynamic EEG and infraslow physiological processes showed confirmatory improvement. A reduction in alcohol craving and longer alcohol-free remission times were also seen. Although there were some benefits in the 16 patients with the parasympathetic type of autonomic disorders, they were smaller and less stable. There were no beneficial effects of PHT or standard therapy in a group of five young patients with a malignant, rapidly progressive form of alcoholism. We conclude that PHT is useful in acute alcohol withdrawal and in the treatment of the asthenic-autonomic syndrome (during the rehabilitative phase) in patients with sympathetic type of autonomic disorder. Further clinical evaluation and use of PHT in alcohol withdrawal and rehabilitation are indicated.

Epidural and Intravenous Opioid-induced Neuroexcitation

Epidural and Intravenous Opioid-induced Neuroexcitation

Phenytoin increases markers of osteogenesis for the human species in vitro and in vivo.

Phenytoin therapy is a well recognized cause of gingival hyperplasia, a condition characterized by increased gingival collagen synthesis, and may also cause acromegalic-like facial features. Based on these clinical findings suggestive of anabolic actions, we sought to test the hypothesis that phenytoin acts on normal bone cells to induce osteogenic effects. To test the direct actions of phenytoin on human bone cells, we measured the dose responses to phenytoin for [3H]thymidine incorporation, cell number, alkaline phosphatase specific activity, and collagen synthesis in human hip bone-derived cells. Phenytoin significantly and reproducibly increased [3H]thymidine incorporation, cell number, alkaline phosphatase specific activity, and collagen synthesis in a biphasic manner with optimal stimulatory doses between 5-10 mumol/L. Thus, micromolar concentrations of phenytoin can act directly on human bone cells to stimulate osteoblast proliferation and differentiation. We next sought to test the hypothesis that phenytoin stimulates bone formation in humans in vivo. Accordingly, three serum biochemical markers of bone formation, i.e. osteocalcin, skeletal alkaline phosphatase, and procollagen C-terminal extension peptide, were measured in 39 male epileptic patients, 20-60 yr of age, with an average duration of phenytoin therapy of 10.5 +/- 1.62 yr (mean +/- SEM). In this group of patients, the mean serum phenytoin level was 9.56 +/- 0.90 mg/L (mean +/- SEM; equivalent to 34.9 +/- 3.3 mumol/L). Thirty apparently healthy male subjects of similar age and taking no medication were included as controls. Serum calcium, 25-hydroxyvitamin D3, and PTH levels in the phenytoin-treated patients were not significantly different from those in the age-matched controls and were within the clinical laboratory normal range of our hospitals, indicating that the patients did not develop hypocalcemia, vitamin D deficiency, or secondary hyperparathyroidism. Serum levels of osteocalcin, skeletal alkaline phosphatase, and procollagen peptide in the phenytoin-treated patients were significantly increased compared to those in the age-matched subjects; in each case these biochemical markers were significantly correlated with the serum phenytoin level, but not with the dose or duration of phenytoin treatment. These findings are consistent with the interpretation that phenytoin increases the bone formation rate in humans in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of phenytoin in children with acute neurotrauma.

To determine the pharmacokinetics of intravenous phenytoin in critically ill infants and children with acute neurologic injury. A prospective, descriptive study. A pediatric intensive care unit. Sixteen children, 0.5 to 16 yrs of age (mean 7.6), with various types of acute neurologic injuries, receiving intravenous phenytoin therapy. Blood samples were collected to measure total and free phenytoin concentrations in plasma. A 24-hr urine collection was made to determine the concentrations of the major metabolite of phenytoin. In 12 children who survived the acute illness, a lower-than-predicted Michaelis-Menten constant (Km) and higher-than-predicted maximum rate of metabolism (Vmax) were observed. Initial free phenytoin fractions ranged between 0.08 and 0.15. In the eight patients who had additional free fractions measured, six patients demonstrated an increase (9.1% to 34% increase) in free fraction, while two patients demonstrated a decrease (1.8% and 19.8% decrease) in free fraction. The ratio of amount of phenytoin to phenytoin plus 5-(p-hydroxyphenyl)-5-phenylhydantoin excreted in the urine in a 24-hr urine collection demonstrated a wide inter-patient variability. There was no correlation in the difference between the predicted and calculated Km and Vmax values and Glasgow Coma Score, circulating albumin concentration, or concomitant medications. Based on the average Km and Vmax values of the children enrolled in our study, it appears that children with neurologic injury between the ages of 0.5 and 9 yrs may require dosages of at least 8 to 10 mg/kg/day, and children aged 10 to 16 yrs may require 6 to 8 mg/kg/day to attain therapeutic phenytoin concentrations.

Phenytoin-folic acid interaction.

To review information regarding the dual and interdependent drug-nutrient interaction between phenytoin and folic acid and other literature involving phenytoin and folic acid. Information was retrieved from a MEDLINE search of English-language literature conducted from 1983 (time of the last review) to March 1995. Search terms included folic acid, phenytoin, and folic acid deficiency. Additional references were obtained from Current Contents and from the bibliographies of the retrieved references. All human studies examining the effects of phenytoin on serum folate concentrations and folic acid supplementation on serum phenytoin concentrations were selected. These included studies of patients with epilepsy and healthy volunteers as well as case reports. Case reports were included because of the extensive length of time needed to study this drug interaction. Data extracted included gender, dosing, serum folate concentrations if available, pharmacokinetics, and adverse events. Serum folate decreases when phenytoin therapy is initiated alone with no folate supplementation. Folic acid supplementation in folate-deficient patients with epilepsy changes the pharmacokinetics of phenytoin, usually leading to lower serum phenytoin concentrations and possible seizure breakthrough. Folate is hypothesized to be a cofactor in phenytoin metabolism and may be responsible for the "pseudo-steady-state," which is a concentration where phenytoin appears to be at steady-state, but in reality, is not. Phenytoin and folic acid therapy initiated concomitantly prevents decreased folate and phenytoin obtains steady-state concentrations sooner. Folic acid supplementation should be initiated each time phenytoin therapy commences because of the hypothesized cofactor mechanism, decreased adverse effects associated with folate deficiency, and better seizure control with no perturbation of phenytoin pharmacokinetics.

Dilantin-associated lymphadenopathy. Spectrum of histopathologic patterns.

The association of Dilantin (hydantoin) therapy and lymphadenopathy in the form of "pseudolymphoma" or malignant lymphoma has been reported primarily in the clinical literature in single case reports or small series, most of which contain very few pathologic details. We studied a series of 25 lymph node lesions collected at the Armed Forces Institute of Pathology from 1965 to 1991 that were suspected to be related to intake of the antiseizure medication Dilantin. Each case had been coded by the Environmental and Toxicology Department according to the so-called "operational degrees of certainty," which gives the possibility that a pathologic change is the result of a drug. Of the 25 cases, six were coded as probable, 17 as possible, and two as coincidental. The male:female ratio was 11:14, and patient ages ranged from 24 to 81 years (median, 53 years). Documented lymphadenopathy developed 1 week to 30 years (median, 5 years) after the start of Dilantin. The histologic features were reviewed in 25 of 25 cases, and the immunophenotypic data was available in 18 of 25. Fifteen of 25 cases showed a benign histology, which we primarily classified according to the presence or absence of immunoblastic hyperplasia. Seven cases were non-Hodgkin's lymphoma, and three were Hodgkin's disease. In two of five cases for which sequential biopsies were available for review, there was progression from paracortical hyperplasia to malignant lymphoma. Our report describes the clinicopathologic features of 25 cases of Dilantin-associated lymphadenopathy and confirms the heterogeneity and nonspecificity of these histologic patterns.

Case Report

We report a clinically relevant suspected interaction between acyclovir and the antiepileptic drugs phenytoin (PHT) and valproic acid (VPA). In a child receiving PHT and VPA therapy, a 6-day acyclovir treatment reduced PHT and VPA plasma concentrations to subtherapeutic values. This probably worsened both clinical status and electroencephalographic recordings observed in this patient. We suggest that the interaction occurs at gastrointestinal level with a reduction of PHT and VPA oral bioavailability during antiviral treatment.

Management of Meralgia Paresthetica

To the Editor: We read with interest a case report by Kallgren and Tingle [1] on meralgia paresthetica mimicking lumbar radiculopathy. Meralgia paresthetica is essentially an entrapment of the lateral femoral cutaneous nerve with subsequent signs and symptoms in the distribution of the nerve. In our experience too, this neurologic syndrome very often mimics entities such as lumbar root compression or a femoral neuropathy as also reported by other authors [2,3]. Once diagnosed, the management of meralgia paresthetica poses a formidable challenge to the treating clinician. We describe 40 patients with clinical features of meralgia paresthetica referred to our Pain Clinic over a period of 6 yr (February 1988 to December 1993) who were managed by a multimodality regimen. The clinical diagnosis of meralgia paresthetica was based on the presence of the following signs and symptoms: (a) unpleasant paresthesias/numbness/burning sensation/dysesthesias/pain over the anterolateral aspect of the thigh and (b) exacerbation of symptoms on walking, standing, or extending the hips. All patients underwent a detailed neurologic examination, and computerized tomography (CT) scan/magnetic resonance imaging (MRI) was performed to rule out any radicular lesion of the lumbar roots. Fifteen patients were subjected to electrophysiologic studies of the lateral femoral cutaneous nerve, and slowing of conduction velocity with abnormal sensory action potentials was considered diagnostic of meralgia paresthetica. This clinical syndrome was predominantly observed in males (67.5%). The duration of symptoms ranged from 1 mo to 16 mo (mean, 4.3 mo). No associated factors were found in 18 patients (45%), while another 22 patients (55%) had aggravating factors such as obesity (12 patients) and history of surgical trauma (5 patients) just prior to development of symptoms. Twelve patients (37.5%) were being treated for radicular pain due to a prolapsed lumbar intervertebral disk and were referred only after CT scan/MRI failed to detect the radiculopathy. Unpleasant paresthesias over the anterolateral aspect of the thigh were the major complaint (85%). However, 30 patients (75%) also complained of tingling or throbbing pain in the thigh. Hypersensitivity was present in 25% of patients, who even disliked the touch of a cloth in the affected area. The treatment plan followed in the Pain Clinic was as follows. A diagnostic lateral femoral cutaneous nerve block was performed with 8 mL of 0.25% bupivacaine. In the event of relief of symptoms, repeated blocks on alternate days were given with 0.25% bupivacaine combined initially with a depot steroid methylprednisolone acetate in divided doses of 20 mg each, up to a maximum of 80-120 mg. The total number of blocks varied in each patient, but a minimum of five blocks were administered to all the patients. Next, oral diphenylhydantoin in a dose range of 100-300 mg daily in divided doses was administered simultaneously to all patients. The average duration of diphenylhydantoin therapy varied from 10 to 12 wk. The response to treatment was determined at weekly intervals by using verbal intensity scale (VIS) and the modified visual analog scale (VAS). Thirty-four patients (85%) had complete relief of unpleasant paresthesias and pain within 10 wk of initiating treatment. These patients also showed a disappearance of the area of the sensory loss on neurologic examination. Two patients (5%) had relief of pain but no diminution of unpleasant paresthesias, while four patients (10%) did not have any relief in symptoms even up to 6 mo of treatment. Twelve-month followup was possible in 28 patients who showed no recurrence of symptoms. Although a single block of the lateral femoral cutaneous nerve has been reported to be effective in controlling symptoms for prolonged periods [1,4], our experience has shown that even multiple blocks (more than five) with local anesthetics alone were not effective in controlling the pain and paresthesia. Repeated nerve blocks with a local anesthetic (bupivacaine) and a depot steroid methylprednisolone acetate at the site of entrapment helped in restoring normal conduction across the nerve. It is suggested that an afferent efferent neuronal loop at the spinal segmental level is broken by repeatedly blocking the nerve. Local steroids reduce the hyperexcitability of neurons and C-fibers [5]. Diphenylhydantoin is a membrane-stabilizing drug that prolongs the recovery time of activated Na+ channels and thus selectively reduces or prevents repetitive neuronal firing. Besides, diphenylhydantoin also has modulatory effects on synaptic transmitter release and postsynaptic excitability [6]. G. P. Dureja, MD Veena Gulaya, MD T. S. Jayalakshmi, MD P. Mandal, MD Pain Clinic, Department of Anaesthesiology, All India Institute of Medical Sciences, New Delhi 110 029, India

Paediatric renal transplantation non-compliance.

The aim of this study was to quantify and where possible objectively confirm the magnitude of non-compliance (NC) in our paediatric renal transplant recipients. A total of 94 paediatric transplants were performed between 1984 and 1989; 17 were excluded due to graft loss (2), death (3), oxalosis (2) and transfer to the adult unit (10). NC was assessed as missed clinic visits plus medication shortages or actual admission of NC. NC was found in 22% (17/77) of transplanted patients. NC showed no correlation with parental marital status, sex, distance lived from the hospital, pre-emptive transplant status or total lymphoid irradiation. Most NC was peripubertal with a smaller NC in the late teenager group. Social class correlated positively with NC; 82.3% of NC was from social classes III and IV, who formed 52.4% of the patients. NC in social class II (3/26) was significantly different from social class IV (12/24) (P = 0.01); 91% of black patients with NC were from social class IV. Race, corrected for social class, failed to reach significance (P > 0.05). Confirmation of compliance was sought from retrospective cyclosporin A (CsA) trough levels (twice daily dosage). Concomitant phenytoin therapy and CsA given as a daily dosage were excluded as significant confounding variables. The CsA dosage was not significantly different between the compliant (C) and patients with NC. Patients with NC were 8 times more likely to have a CsA level < 10 ng/ml (P = 0.0026) than C patients.(ABSTRACT TRUNCATED AT 250 WORDS)